6-Fluoro-4-oxochroman-2-carboxylic acid

The title compound, C10H7FO4, is an intermediate in the synthesis of the drug Fidarestat, (2S,4S)-2-aminoformyl-6-fluoro-spiro[chroman-4,4′-imidazolidine]-2′,5′-dione. The dihydropyranone ring adopts an envelope conformation with the asymmetric C atom in the flap position. In the crystal, the molecules are linked into zigzag chains along [100] by O—H⋯O hydrogen bonds and C—H⋯π interactions involving the benzene ring.

Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: CI2987). shows strong inhibition to aldose reductases to cure incurable complications of diabetes (Mitsuru et al., 2000;Mealy, 1996).
Our interests in synthesizing Fidarestat prompted us to develop an efficient methodology for synthesizing (S)-6-fluoro-4oxochroman-2-carboxylic acid. In our synthetic work, we obtained the title compound, which is similar to those reported in the literature (Kurono et al., 1989;Yamaguchi et al., 1994). Its crystal structure is reported here.
The dihydropyranone ring adopts an envelope conformation with the asymmetric C atom in the flap position ( Fig. 1). (Table   1) involving the benzene ring.

Experimental
To a stirred solution of (2S,4R)-2-(1',2'-Dihydroxyethyl)-6-fluoro-chroman-4-one (10.7 g, 0.05 mol) in 300 ml of anhydrous benzene at room temperature was added lead tetraacetate (22.2 g, 0.05 mol). After 30 min, the solution was filtered and the filtrate was evaporated in vacuum to the residue. To the solution of 2% aqueous silver nitrate (651 ml, 0.07 mol) was added 5% aqueous sodium hydroxide (120 ml, 0.16 mol), and then generated the black precipitate immediately. To this stirred solution at room temperature was added, dropwise over 5 min, 4% ammonia water (520 ml, 0.16 mol). The black precipitate disappeared. The residue described above was dissolved in small amounts of THF and then added in this stirred solution at 323-333 K. After 10 min, the solution was filtered, and the precipitate was washed with water. The filtrate was acidified to pH 1 with 6 N aqueous hydrochloric acid, and then extracted with ethyl acetate. The organic extracts were dried (MgSO 4 ) and then concentrated under reduced pressure. The residue was mixed with a mixture of ethanol and water, and left to crystallize 8.7 g (83%) of 6-Fluoro-4-oxochroman-2-carboxylic acid. Colourless crystals suitable for X-ray analysis were obtained by slow evaporation in ethanol at room temperature.

Refinement
H atoms were positioned geometrically (O-H = 0.84 and C-H = 0.95-1.00 Å) and refined using a riding model, with U iso (H) = 1.2U eq (C) and 1.5U eq (O). In the absence of significant anomalous scattering, Friedel pairs were merged prior to the final refinement. Nine reflections that were affected by the beamstop were discarded.
supplementary materials sup-2 Figures   Fig. 1. The molecular structure of the title compound, with displacement ellipsoids drawn at the 50% probability level. Refinement. Refinement of F 2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F 2 , conventional R-factors R are based on F, with F set to zero for negative F 2 . The threshold expression of F 2 > σ(F 2 ) is used only for calculating Rfactors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F 2 are statistically about twice as large as those based on F, and R-factors based on ALL data will be even larger.